caspase-13 Inhibitors

Chemical inhibitors of caspase-13 can influence its activity in various ways, depending on the specific molecular interactions and processes they target. Z-DEVD-FMK, Z-VDVAD-FMK, Z-LEHD-FMK, and Z-IETD-FMK are all peptide-based inhibitors that mimic the natural substrates of caspases. These inhibitors bind irreversibly to the active site cysteine of caspase-13, which is crucial for its protease activity. Z-DEVD-FMK, for example, is traditionally known for its strong affinity toward caspase-3 but can also inhibit caspase-13 due to the similarity in substrate recognition sites between these caspases. Z-VDVAD-FMK operates similarly, covalently modifying the active site and thus preventing caspase-13 from cleaving its specific substrates, resulting in the inhibition of its role in apoptosis. Z-LEHD-FMK acts upstream by binding to caspase-9, which is a known initiator of the caspase cascade that ultimately activates caspase-13. Inhibition of caspase-9 thus hinders the activation of caspase-13. Z-IETD-FMK targets caspase-8, a protease that can activate the proenzyme form of caspase-13, and by obstructing this activation, it indirectly inhibits caspase-13.

Other inhibitors such as Q-VD-OPh, Emricasan, and VX-765 are more broad-spectrum in their caspase inhibition. Q-VD-OPh can inhibit caspase-13 by binding directly to its active site, preventing the proteolytic cleavage of caspase-13's substrates. Emricasan prevents the formation of the apoptosome, thereby averting the subsequent activation of caspase-13. VX-765 selectively inhibits caspase-1, which is involved in the inflammasome pathway; by doing so, it can indirectly inhibit the activation of caspase-13, as the inflammasome pathway is known to activate downstream caspases like caspase-13. Other chemical inhibitors such as Crizotinib, Parthenolide, PD98059, SB203580, and SP600125 target different signaling pathways that indirectly influence the activity of caspase-13. Crizotinib, by inhibiting ALK-positive anaplastic large cell lymphoma, may reduce activation of downstream caspases including caspase-13. Parthenolide targets the NF-kB pathway, a crucial regulator of apoptosis, and by doing so, it modulates the cellular pathways that control caspase activation, leading to decreased activation of caspase-13. PD98059, SB203580, and SP600125 inhibit various kinases like MEK, p38 MAPK, and JNK, respectively, which are part of the signaling pathways involved in stress response and apoptosis. Their inhibition can lead to reduced activation of caspase-13, as this protein is situated downstream of these signaling cascades. By targeting these pathways, the compounds can decrease the cellular events that result in caspase-13 activation, thereby functionally inhibiting caspase-13.